Physiological Basis of Functional MRI

描述（由申请人提供）：我们的总体目标是发展对人脑中血流和能量代谢耦合的定量理解，并开发用于评估健康和疾病中这种耦合的定量方法。功能性磁共振成像（fMRI）通过提供一种灵敏的、非侵入性的脑活动绘图工具，彻底改变了对人脑工作状态的研究。该方法利用MR信号对脱氧血红蛋白含量的局部变化的敏感性，称为血氧水平依赖（BOLD）效应。BOLD效应背后的中枢生理现象是，在大脑活动增加期间，脑血流量（CBF）的增加超过脑氧代谢率（CMRO 2）。然而，尽管它的成功作为一个映射工具，定量解释的幅度BOLD响应作为潜在的生理变化的幅度的反映是有问题的，因为我们的理解差的变化CBF/CMRO 2耦合。在之前的支持期间，我们实施并评估了校准的BOLD方法，除了神经激活外，还测量了局部CBF和BOLD对轻度高碳酸血症的反应，以测量CBF和CMRO 2的耦合。我们的工作强调了CBF/CMRO 2耦合比对于解释整个大脑区域和疾病中的BOLD反应的重要性，并且还证明了校准的BOLD方法为定量评估基础研究和潜在临床环境中的大脑生理学提供了强大的工具。解释BOLD反应的一个核心问题是，我们不知道健康人脑中CBF/CMRO 2耦合的变化程度，本提案的主要目标是确定这种变化。我们以前的研究结果是一致的假设，CBF/CMRO 2耦合比增加更强的刺激，这是符合目前的想法，CBF是由输入的神经活动驱动的区域，而CMRO 2响应的总能量需求的全部诱发活动。我们将在健康人脑中测试这一假设，实验范式旨在操纵所涉及的神经活动类型，并测试CBF和CMRO 2反应的解离。所提出的实验利用对比敏感度和时间频率调谐效应（目标1），适应效应（目标2），抑制效应和负BOLD信号（目标1和3）。此外，我们将通过开发一个更完整的BOLD响应数学模型（包括血管内信号变化和动脉血容量变化的影响）来改进当前的校准BOLD方法，并测试一种替代高氧技术作为高碳酸血症的替代校准方法（目标4）。这些目标的实现将为BOLD-fMRI的基础科学研究和临床应用奠定坚实的生理基础。公共卫生相关性：一个校准的功能磁共振成像方法有可能提供一个定量探针的脑生理学通过测量血流量和氧代谢的变化。这个工具可以作为一个“压力测试”来评估大脑功能，以早期发现功能障碍，并监测疾病的进展或对药物和治疗的反应。我们的目标是通过扩展和改进方法，并通过更好地了解健康大脑中的流量和代谢如何耦合，为这些应用奠定基础。

DESCRIPTION (provided by applicant): Our overall goal is to develop a quantitative understanding of the coupling of blood flow and energy metabolism in the human brain, and to develop quantitative methods for assessing this coupling in health and disease. Functional magnetic resonance imaging (fMRI) has revolutionized the study of the working human brain by providing a sensitive, non-invasive tool for mapping brain activity. The method exploits the sensitivity of the MR signal to local changes in deoxy-hemoglobin content, called the Blood Oxygenation Level Dependent (BOLD) effect. The central physiological phenomenon underlying the BOLD effect is that cerebral blood flow (CBF) increases more than the cerebral metabolic rate of oxygen (CMRO2) during increased brain activity. Yet despite its success as a mapping tool, quantitative interpretation of the magnitude of the BOLD response as a reflection of the magnitude of underlying physiological changes is problematic because of our poor understanding of the variability of CBF/CMRO2 coupling. During the previous period of support we implemented and evaluated a calibrated-BOLD approach, measuring local CBF and BOLD responses to mild hypercapnia in addition to neural activation, to measure the coupling of CBF and CMRO2. Our work highlighted the importance of the CBF/CMRO2 coupling ratio for interpreting BOLD responses across brain regions and in disease, and also demonstrated that the calibrated-BOLD approach provides a powerful tool for quantitatively assessing brain physiology for both basic research and potentially in clinical settings. A central problem for the interpretation of the BOLD response is that we do not know to what degree CBF/CMRO2 coupling varies in the healthy human brain, and the primary goal of this proposal is to determine that variability. Our previous results are consistent with the hypothesis that the CBF/CMRO2 coupling ratio increases for stronger stimuli, which is consistent with current ideas that CBF is driven by the input neural activity to a region while CMRO2 responds to the total energy needs of the full evoked activity. We will test this hypothesis in the healthy human brain with experimental paradigms designed to manipulate the types of neural activity involved and test for a dissociation of the CBF and CMRO2 responses. The proposed experiments exploit contrast sensitivity and temporal frequency tuning effects (Aim 1), adaptation effects (Aim 2), and inhibitory effects and negative BOLD signals (Aims 1 and 3). In addition, we will improve the current calibrated-BOLD methodology by developing a more complete mathematical model for the BOLD response that includes effects of intravascular signal change and arterial blood volume changes, and test an alternative hyperoxia technique for calibration as an alternative to hypercapnia (Aim 4). Completion of these goals will lay a solid physiological foundation for both basic science studies with BOLD-fMRI and clinical applications of fMRI. PUBLIC HEALTH RELEVANCE: A calibrated-fMRI methodology has the potential to provide a quantitative probe of brain physiology by measuring blood flow and oxygen metabolism changes. This tool can serve as a "stress-test" to evaluate brain function for early detection of dysfunction and for monitoring the progression of disease or the response to drugs and therapy. Our goal is to lay the groundwork for these applications by extending and improving the methodology and by gaining a better understanding of how flow and metabolism are coupled in the healthy brain.